FDA's requirement for large, cardiovascular safety trials for all new diabetes and obesity drugs has created a "cottage industry" that some see as necessary but others feel drives up drug costs.
During last year’s Scientific Sessions of the American Diabetes Association in Boston, Silvio Inzucchi, MD, of the Yale Diabetes Center called cardiovascular outcomes trials the new “cottage industry” of the research world that studies drugs to treat type 2 diabetes (T2D).
In recent years, these large, long-term safety trials have become a mainstay of ADA’s annual meeting and will be so again next month, when the 76th Scientific Sessions convene in New Orleans.
Results from the LEADER trial (liraglutide effect and action in diabetes: evaluation of cardiovascular outcome results), will be presented June 13, 2016, and more information from the groundbreaking EMPA-REG Outcome trial, which found that the SGLT2 inhibitor empagliflozin has a cardiovascular benefit, will follow on June 14, 2016. Results from EMPA-REG Outcome trial were the talk of the September 2015 meeting of the European Association for the Study of Diabetes in Stockholm, Sweden.
As Inzucchi explained last year, the cardiovascular outcomes trial or “CVOT” has become a highlight of scientific meetings because of a set of events that drove their creation: notably, the rise and fall of rosiglitazone (Avandia), which was a blockbuster until a meta-analysis published in the New England Journal of Medicine said the drug presented an increased heart attack risk.
FDA limited sales of rosiglitazone while conducting a review that ultimately found no cardiovascular benefit or risk from the drug. But as reported by Evidence-Based Diabetes Management, (EBDM) the damage was done, and physicians wary of being sued moved on to other therapies.
The rosiglitazone episode led to a new FDA guidance in 2008, which called for the CVOT for new diabetes and obesity therapies. These massive trials—conducted worldwide and involving at least 5000 patients—would mostly occur in the post-marketing phase.
Positive post-marketing results can distinguish 1 drug in a class from its competitors. That was the case at the 2015 ADA sessions, when full results for sitagliptin (Januvia), involving 14,000 patients, showed the DPP-4 inhibitor did not cause adverse cardiovascular effects, including hospitalization due to heart failure. (Coverage of the TECOS trial can be found here.)
Today, CVOT results don’t always come after FDA approval. Inzucchi made his comments during presentation of results of the ELIXA trial (evaluation of lixisenatide in acute coronary syndrome). That study of the GLP-1 receptor agonist found no risks or benefits for patients taking the T2D therapy. Since last summer, lixisenatide’s maker, Sanofi, has filed a new drug application with FDA, marking the first time that a pharmaceutical sponsor has sought such an approval with the CV results already in hand.
Sanofi isn’t alone. Just last week Intarcia Therapeutics announced top-line results of its cardiovascular safety trial for ITCA 650, the novel matchstick-size device that delivers continuous, microscopic doses of exenatide—and approved therapy—while overcoming the adherence issues that plague T2D care. The company said it has results in hand to proceed for FDA approval.
ITCA 650’s major clinical results were a highlight of the 2015 ADA meeting in Boston; a company spokesman said Monday the CV results will not be presented in New Orleans but other results will be outlined in scheduled talks.
Depending on the therapy, this approach avoids what happened last summer when FDA handled approvals for competing PCSK9 inhibitors, the new, very expensive drugs to treat high cholesterol. Regulators limited labels on both injections, evolocumab and alirocumab, while awaiting long-term cardiovascular results that won’t be ready until 2017.
The CVOT has received both praise and criticism.
Harvard’s Mark Pfeffer, MD, PhD, said while presenting the ELIXA results that a “cloud of suspicion” hangs over new diabetes drugs, and as a result, “You can never, never really have enough safety data.”
But in September 2013, G. Alexander Fleming, MD, a former FDA regulator, told EBDM that while proving safety is important, the trials are expensive and add 3-4 years to the review process. “Should this be a slavish requirement?” he said during the interview. “If not other drug in the class has shown a problem, it’s probably not a good idea, not just from the standpoint of cost but in terms of consuming patients who are a scarce resource.”
At the most recent gathering of Patient-Centered Diabetes Care, presented by The American Journal of Managed Care and Joslin Diabetes Center, Lonny Reisman, MD, of HealthReveal outlined out more widespread use of patient data could allow for what he called “machine studies” that could someday serve as a substitute for these huge clinical trials.
While the CVOT is becoming more routine, it’s essential to listen to the full results for hints of what’s coming next. Inzucchi dropped what turned out to be an important clue during his commentary after the ELIXA results when he said that it might be “naïve” for doctors in diabetes care to think they can improve CV outcomes, given the patient profiles. But, he said, if a therapy were to achieve that, “Only then would we have achieved the holy grail.”
It turned out the “holy grail” was just around the corner: the results for empagliflozin arrived just 3 months later.